ERβ regulation of NF-κB activation in prostate cancer is mediated by HIF-1

We examined the regulation of NF-kappa B in prostate cancer by estrogen receptor beta (ER beta) based on the inverse correlation between p65 and ER beta expression that exists in prostate carcinomas and reports that ER beta can inhibit NF-kappa B activation, although the mechanism is not known. We demonstrate that ER beta functions as a gate-keeper for NF-kappa B p65 signaling by repressing its expression and nuclear translocation. ER beta regulation of NF-kappa B signaling is mediated by HIF-1. Loss of ER beta or hypoxia stabilizes HIF-1 alpha, which we found to be a direct driver of IKK beta transcription through a hypoxia response element present in the promoter of the IKK beta gene. The increase of IKK beta expression in ER beta-ablated cells correlates with an increase in phospho-I kappa B alpha and concomitant p65 nuclear translocation. An inverse correlation between the expression of ER beta and IKK beta/p65 was also observed in the prostates of ER beta knockout (BERKO) mice, Gleason grade 5 prostate tumors and analysis of prostate cancer databases. These findings provide a novel mechanism for how ER beta prevents NF-kappa B activation and raise the exciting possibility that loss of ER beta expression is linked to chronic inflammation in the prostate, which contributes to the development of high-grade prostate cancer.